Dysregulated dopamine metabolism in LRRK2 mutants

Author

Chia, Xin Tian

Date of Issue

2015

School

School of Biological Sciences

Related Organization

Singapore General Hospital, Department of Clinical Research

Abstract

Background: LRRK2 mutations are the most common genetic cause of Parkinson’s disease (PD). Previously, a compelling link between dopamine metabolic dysregulation and PD pathogenesis has been established. Specifically, dopamine synthesis enzymes were reportedly down-regulated in LRRK2 mutants G2019S and G2385R. Approach: Herein, the dysregulation of dopamine metabolism was further characterized in the dopamine degradation pathway of LRRK2 mutants. Protein expression of degradative enzymes (COMT and MAO) was determined using western immunoblot. Intracellular dopamine level was analysed using HPLC, while intracellular ROS and neuronal viability were monitored using cellular assays. Results: No significant changes were found in COMT and MAO-B protein levels between WT and LRRK2 mutants. Whereas, reduced dopamine levels in LRRK2 variants could indicate that dopamine homeostasis is impaired. ROS and neurotoxicity were evidently increased in LRRK2 mutants, and further enhanced under oxidative stress. Conclusion: Together with previous studies, the findings support the dysregulation of dopamine metabolism in LRRK2 mutants, as degradative enzymes were disproportional to the down-regulated synthesis enzymes. Enhanced neurotoxicity in LRRK2 mutants contends that dysregulated dopamine metabolism might underlie PD vulnerability, by increasing ROS generation, and thus potentiating neurotoxicity. Hence, the dysregulation of dopamine metabolism could modulate the neuronal biochemical environment to enhance PD pathogenesis.